Classification of the disorders of hemoglobin

Abstract

Over the years, study of the disorders of hemoglobin has served as a paradigm for gaining insights into the cellular and molecular biology, as well as the pathophysiology, of inherited genetic disorders. To date, more than 1000 disorders of hemoglobin synthesis and/or structure have been identified and characterized. Study of these disorders has established the principle of how a mutant genotype can alter the function of the encoded protein, which in turn can lead to a distinct clinical phenotype. Genotype/phenotype correlations have provided important understanding of pathophysiological mechanisms of disease. Before presenting a brief overview of these disorders, we provide a summary of the structure and function of hemoglobin, along with the mechanism of assembly of its subunits, as background for the rationale and basis of the different categories of disorders in the classification.

Figure 1.

Impact of surface charge on hemoglobin assembly. (A) Effect of charge on the proportion of abnormal hemoglobin in individuals heterozygous for 105 stable β-globin variants. Each data point represents a mean value for a given variant. Substitutions involving a histidine residue were scored as a change of one half charge. The “−1” group differs significantly from the “+1” group (P < 0.001). (B) Effect of α-thalassemia on the proportion of seven positively charged β-subunit variants (blue) and three negatively charged variants (red). (Updated from Bunn and McDonald 1983 and Bunn 1987.)